Pyxinol bearing amino acid residues: Easily achievable and promising modulators of P-glycoprotein-mediated multidrug resistance
| Autor: | Hongbo Wang, Jingxian Sun, Gao Meng, Gangqiang Yang, Zou Zongji, Ren Ruiyin, Conghui Wang, Zhang Chen, Zhihua Song, Liu Shuqi, Hao Xie, Qi Qu, Yupeng Qi |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Sapogenins
Paclitaxel Cell Survival Antineoplastic Agents Apoptosis Molecular Dynamics Simulation 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Catalytic Domain Cell Line Tumor Drug Discovery polycyclic compounds Humans ATP Binding Cassette Transporter Subfamily B Member 1 Amino Acids 030304 developmental biology P-glycoprotein Pharmacology 0303 health sciences Methionine Binding Sites integumentary system biology 010405 organic chemistry Chemistry Organic Chemistry Transporter General Medicine Cell Cycle Checkpoints 0104 chemical sciences Multiple drug resistance Biochemistry Docking (molecular) Drug Resistance Neoplasm Cancer cell biology.protein Efflux |
| Zdroj: | European journal of medicinal chemistry. 216 |
| ISSN: | 1768-3254 |
| Popis: | The P-glycoprotein (Pgp) is a major transporter involved in multidrug resistance (MDR) of cancer cells leading to chemotherapy failure. In our previous study, we demonstrated that the amide derivatives of pyxinol are promising modulators against Pgp-mediated MDR in cancer. In the present study, we designed and synthesized novel pyxinol derivatives linked to amino acid residues. We evaluated MDR (paclitaxel (Ptx) resistance) reversal potency of forty pyxinol derivatives in KBV cells and analyzed their structure-activity relationships. Half of our derivatives sensitized KBV cells to Ptx at non-toxic concentrations, among which the pyxinol compound bearing a methionine residue (3c) exhibited the best activity in MDR reversal. Compound 3c was found to possess high selectivity toward Pgp and sensitize the KBV cells to Pgp substrates by blocking the efflux function of Pgp. This manifestation may be attributed to its high binding affinity with Pgp, as suggested by docking studies. Overall, the biological profile and ease of synthesizing these pyxinol derivatives render them promising lead compounds for further development for Pgp-mediated MDR. |
| Databáze: | OpenAIRE |
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